This is the 35 USC 371 national stage of international application PCT/FR97/00989 filed on Jun. 4, 1997, which designated the United States of America.
The present invention provides a process for preparing an injectable pharmaceutical preparation, a device for implementing said process and the product obtained by implementing the process by means of the device.
It is known that injectable forms are immediately bioavailable and constitute a potential passive mode of administration for the patient and an ideal treatment in urgent cases.
Another important reason for the development of parenteral forms is the use of active principles (AP) which are degraded and/or not significantly absorbed by the oral route.
Of all these AP which, for various reasons, require an injectable form, many of them are unstable in aqueous media, whether in solution, suspension or dispersion.
In order to avoid hydrolysis and all the physico-chemical problems associated with a liquid presentation (precipitation, aggregation, adsorption, crystallisation), a presentation is often used in which the AP is preserved in a solid, dried or freeze-dried form.
The preparation of the liquid form required for injection then takes place extemporaneously, just prior to injection.
This preparation consists in hydrating the solid form with the liquid medium for solubilisation or suspension of the AP.
Traditionally, this operation is carried out in a sealed bottle which contains the solid form. The liquid is introduced into the bottle by a syringe, the needle of which is capable of piercing a stopper-septum.
The liquid form is then recovered in the syringe so that it can be injected.
The time required for this delicate operation and the risks of contamination it involves led experts in medical technology to devise devices for making extemporaneous preparation simpler and more reliable, and for using the fewest possible components.
Along such lines, the patents EP-A-0 664 136, DAIKYO SEIKO, EP-0 599 649 PHARMACIA, WO-95 11051 disclose a bicompartmental or xe2x80x9cby-passxe2x80x9d syringe which combines in the same syringe the liquid medium and the solid form which will be directly rehydrated in the syringe before injection.
Similarly, certain producers propose devices which combine the bottle with the syringe and control the satisfactory execution of the preparation (French patents DEBIOTECH 2 705 898, 2 715 311, 2 717 086).
Certain faults in the traditional systems are not, however, solved by said new devices, which pose problems of loss of preparation in their dead volumes, which do not render rehydration automatic and static but keep it manual and dynamic, that is, the flow of liquid and the transfers after hydration displace the solid form and, in particular, the AP. The injectable form does not, therefore, necessarily have the same distribution or homogeneity as the dry form. This constitutes a problem, particularly in the case of suspensions.
The fact that preparation is dynamic and carried out manually may lead to important differences depending on the operator, the speed with which he acts, the manner in which he loads the liquid and controls the evacuation of the air. Finally, the force with which the solid AP is hydrated is likely to lead to a relatively substantial emulsion of microbubbles of air.
The time allowed for solubilisation or suspension and agitation of the liquid medium determines the homogeneity of the preparation.
In the case of suspensions, poor homogeneity or the onset of sedimentation may lead to dose and administration problems.
The object of the invention is to propose a process for overcoming these various disadvantages.
According to the invention, the process for preparing an injectable preparation is characterised in that a dry form of an active principle under vacuum and a liquid are prepared, and said liquid is introduced into the dry form by suction by virtue of the action of the vacuum in order to form the said injectable preparation.
The process of preparation and packing under vacuum according to the invention avoids the above-mentioned problems (dead volume, manual activation, injectability) and at the same time the problems of injected liquid formulation (homogeneity, degassing).
According to a characteristic of the process, the dry form under vacuum occupies the same volume as the final form obtained after automatic hydration by a corresponding, exactly pre-determined volume of liquid.
According to an embodiment of the process of the invention, a layer of excipient is added to the dry form, said layer being used subsequent to the injectable preparation as a liquid piston in order to push the other layers and to reduce the losses of active principle during injection.
According to another embodiment of the process of the invention, the dry form is packed in a syringe fixed to an automatic rehydration device; in order to prepare the dry form, a liquid containing the active principle is frozen, a specific quantity of excipient solution is added to the surface of the frozen liquid, this excipient solution is frozen, the whole unit is freeze-dried so as to obtain, between the piston of the syringe and the solid of active principle under vacuum, a volume of freeze-dried product containing only the excipient which, after automatic rehydration and movement of the piston in order to empty the syringe, occupies a dead volume at the bottom of the syringe and of the injection needle at the end of injection.
This process of preparation and packing leads to automatic rehydration: it is sufficient for the user to activate the device for the liquid to restore the solid form to the state it was in prior to drying or freeze-drying. Activation of the device consists in bringing into contact the liquid volume and the solid volume under vacuum. After activation, extemporaneous preparation is automatic, that is, the components of the device move solely under the action of the liquid which is drawn by suction by the vacuum under which the solid formulation is placed.
This property of vacuum packing is independent of the operator, and hydration leads to an immediate return to the situation of the liquid form prior to drying or freeze-drying.
The solid form and active principle remain static during this hydration, that is, they are not displaced by the liquid.
This immediate preparation is thus directly injectable without the need to agitate it, transfer it or expel the air before injection.
This process of preparation and packing may use certain devices or containers currently available, provided that they ensure that the form under vacuum is kept under vacuum until rehydration. The component(s) of the device must allow this rehydration whilst avoiding contact with the ambient air.
This feature also leads to certain specific devices or components for this process of preparation and packing. These devices and components will be described below.
The techniques for vacuum packing the solid form in the device and the packaging are derived from existing techniques (blood sampling tube, packing under a plastic film). This vacuum packing of the solid form and of the AP is, moreover, capable of replacing inert gas blanketing (nitrogen) and improving the stability of the preparation particularly at high temperatures (thermal insulation) and the compatibility with the container (contact insulation).
The above-mentioned advantages of the process and of the devices of the invention, which will be explained below, are particularly important for certain preparations:
For a solid, readily solubilised preparation, the advantage is that of obtaining immediately a degassed liquid preparation without air bubbles.
For a solid preparation which is more difficult to solubilise, either due to its viscosity or due to the time required for solution, the formulation under vacuum avoids the emulsion of air in the liquid, simplifies and accelerates solubilisation.
For a suspension and, more especially, for a sustained-release suspension of microspheres (Decapeptyl 3.75 B.1), the formulation under vacuum avoids the problems of dehomogenisation and the risks of precipitation, hence blocking off whilst reducing the time required for reconstitution.
The pharmaceutical preparation under vacuum and the preloaded device make it possible to reduce considerably the dead volume and hence the losses of active principle.
Finally, for a dispersion and more particularly for semi-solid forms, the very high viscosity of the hydrated form makes it practically indispensable to use a process of preparation and packing under vacuum for the dry form.
The non-liquid or semi-solid aqueous form obtained after hydration under vacuum is, moreover, likely to have salting out properties which are different to and better than those of a form hydrated in air. The fact of not having trapped air in the dispersion makes it possible to reduce the volume for the same quantity (which improves salting out) and avoids rupture of the in situ depot structure which may also modify salting out.
The process, packing and devices are described here for aqueous liquid forms. It goes without saying that the whole of the invention applies with the same advantages to liquid forms (solution, suspension or dispersion) which are reconstituted from a mixture of water-organic solvent, from an organic solvent, or from other liquids such as injectable oils.
The speed of the process of preparation and its realisation in a hermetic packing compensates for the viscosity or the risks of evaporation of certain liquids.
The device for implementing the process according to the invention is characterised in that it comprises means of vacuum packing a dry form, means of packing an extemporaneous rehydration liquid, and of connection between these means in order to add, by suction, the liquid to the dry form.
According to a preferred embodiment, the means of vacuum packing the dry form are a gastight syringe and the means of packing liquid are a reservoir containing a piston.
The syringe is preloaded with the solid form under vacuum, the packing of which allows immediate injection after hydration without agitation, and avoiding the transfer of the solution or suspension through a needle from the preparation reservoir of the liquid to the syringe.
Another advantage of the vacuum-packed devices is that it is thus possible to reduce the volumes of the reservoirs of the liquid and solid whilst increasing the precision of the volume injected.
In fact, the absence of air makes it possible to fill completely the compartment containing the solid. The volume contained in the liquid compartment may be calculated exactly in order to occupy the volume left empty in the preparation plus losses of the device. But this volume may also be in excess because it is the volume of the empty space in the solid that will determine exactly the quantity of liquid required for rehydration.
The device containing the rehydration liquid is advantageously contained in an leakproof reservoir, the volume of which may fall freely as the liquid is transferred to the reservoir of the solid form under vacuum.
This may be obtained easily, in particular, with a cartridge or with a pre-filled syringe, the piston of which moves with the movement of the liquid.
The reservoir may also be composed of a pre-filled flexible plastic bag, the flexible walls of which will follow the movement of the liquid.
The connecting element of the liquid and the vacuum shielded from the ambient air may be composed of a septum, a gate, valve or tap.
One of the characteristics of the method and of the devices is to reduce the dead volumes. This is achieved not only by reducing the volume of the connecting components (liquid-vacuum) or injection components (needle-syringe) but also by virtue of the static rehydration process which makes it possible to occupy the dead volumes with liquid without active principle, and hence without loss of injection.
Thus, the connecting component and/or the needle may be loaded with liquid without active principle in order to eliminate losses.
Moreover, it is possible, by virtue of the same static process, to provide the xe2x80x9cliquid pistonxe2x80x9d without active principle mentioned above, which will occupy the dead volumes of the injection syringe and of the needle after administration, thus making it possible to reduce even further the losses of active principle. This is simply obtained by adding, after freezing the liquid formulation containing the active principle, a calculated volume of a solution of excipient such as mannitol, which will be frozen and freeze-dried at the same time as the formulation. By virtue of static and rapid rehydration, the two liquids, once re-formed, will hardly mix at all and the liquid without active principle will be able to push all the liquid with active principle out of the syringe and the needle (like a xe2x80x9cliquid pistonxe2x80x9d), which will avoid losses.
In all cases (solution, suspension or dispersion), once the solid form has dried or freeze-dried, if the syringe is closed on the injection side by the connecting component, the needle or a septum, the piston is placed under vacuum with or without a blocking system, for example, inside the freeze-dryer. If the syringe is open, it can be vacuum-packed at the time of packaging under plastic film.
Even if the packing of the closed syringe is carried out beforehand under vacuum, it will be best then to pack this syringe under vacuum in such a way that the packaging, and not the syringe, ensures air-tightness during storage. This constitutes a double safety mechanism and also facilitates monitoring of the integrity of the packaging prior to use (opening).
The product or final form obtained after hydration of the solid may take one of the three forms below:
1) Solutions
The active principle combined, for example, with mannitol, is solubilised in water for injectable preparation; the solution is distributed by volume inside the syringes; the syringes are frozen and freeze-dried according to a conventional process and the solid freeze-dried product is vacuum-packed with the syringe, whether or not the syringe has been fixed beforehand to the other components of the extemporaneous rehydration device.
2) Suspensions
In the case of sustained-release microspheres, for example, the dose of microspheres is weighed into the syringe. The volume of dispersion liquid is added. The microspheres are then dispersed mechanically in the liquid. Ultrasonics are preferably used for this dispersion operation. The dispersion is then frozen rapidly, preferably in liquid nitrogen to obtain a homogeneous dispersion of the microspheres in the frozen liquid. The liquid contains the matrix of the freeze-dried product, for example, mannitol. Freeze-drying is carried out to obtain a solid in which the microspheres are suspended by the matrix in the ideal state of homogeneous dispersion of the liquid.
This solid, whether or not it is combined with the components of the automatic device for extemporaneous rehydration, is then vacuum-packed.
3) Dispersion
In the case of a semi-solid implant, for example, the semi-solid Autogel BIM 23014C, the active principle is weighed out inside a gastight metered-dose syringe.
The product obtained by implementing the process and device according to the invention comprises a dry form for parenteral administration and vacuum-packed inside an injection device also containing a liquid volume, ready to be mixed by suction with the dry form in order to reconstitute the injectable preparation.
The dry form may be a freeze-dried form or a powder obtained after removal of a solvent.